A prominent feature of cocaine abuse and dependence disorders is the frequent occurrence of relapse episodes often caused by psychological distress and/or negative emotional affect. Relapse to drug use is commonly modeled in experimental animals using the reinstatement procedure. In this paradigm, animals are first trained to self-administer drugs of abuse via operant responding (e.g. lever-press), and then this responding is extinguished by withholding drug infusions. Once extinguished, responding can be reinstated by exposing the animal to various stimuli, including stress. However, the stressors typically used to reinstate cocaine-seeking behavior in animals are physical or pharmacological in nature, whereas psychosocial stressors more closely resemble the types of stress that typically induce craving and provoke relapse in humans. This is of great concern because numerous studies have indicated that the brain circuitry mediating responses to psychosocial stress may be different from those that mediate responses to other forms of stress. To address this gap in drug abuse research, I developed a novel reinstatement procedure in which cocaine-seeking behavior in rats is triggered by psychosocial, rather than physical or pharmacological, stress. The psychosocial stressor employed in this paradigm is conspecific social defeat, which can be engendered by placing an intruder rat into the home cage of a larger resident territorial rat. The resident will quickly threaten and ultimately foce the intruder to submit. Importantly, the distress experienced by the intruder is thought to closely mirror the types of psychosocial stress that drug abusers experience prior to a relapse episode. I hypothesize that psychosocial stress-induced cocaine seeking is mediated by distinct neural circuitry as compared to other stressors, and likely includes components of a highly- conserved defensive system in the brain. In Aim 1 (K99 phase), I will use c-fos immunohistochemical techniques to map the brain activation patterns produced by cocaine seeking in response to psychosocial or physical stress to identify those regions selectively activated during psychosocial stress-induced reinstatement. In Aims 2 and 3 (R00 phase), I will use the training I acquired during the K99 phase to apply chemical genetic approaches (site-specific expression of designer receptors, DREADDs) to determine whether components of the defensive circuit are causally linked to the observed drug-seeking response. The results of these studies could have a profound impact on our understanding of the interaction between stress and addiction processes, and will lay the foundation for future work aimed at further characterizing the neurobiology underlying psychosocial stress-induced drug-seeking behavior. The ultimate goal of these studies is to identify novel behavioral and/or pharmacotherapeutic treatment strategies to prevent stress-induced drug relapse.